Process for the preparation and manufacture of 6-methoxy-8-(4-amino-1-methylbutylamino)-quinoline



Patented July 22, 1952 2,604,474 o Fl-ce I Pe -cries onyrne PREPARATION AND-- MANUFACTURE OF 6-METH0XY-81-(4F- A-MI-N'O 1 -L1METHYLBUTYLAI\IH\TO.)-

QUINOLINE Robert 'C'. Elderfield, Hastings On'Hudson, and Eleanor Werble,New York, N'. Y'., assignors to the United States of America as represented by the Administrator, Federal Security Agency N Drawing. Application June 8, 1950, Serial No. 166,991

(Granted under the: act of March 3, 1883, as amended April 30, 1928; 370 G. 757) 4 claims;

The invention described. hereinmay; be manu: fa'ctureda andiusedby or for the Governmcntof the United. States. .for; governmental, purposes without :the payment to ,us of any royalty thereon in. accordance with the provisionsof, the act of ApriIiBO, 1928. (ch. 460, 45 Stat. L. 467).

This invention relates to; the production of primaquine Jand'it's homologs; More, particularly, it'r'elates toithe production thereof beginning with readily available raw-materials.

Pri'maquineisethe name given to the chemical identifledf. as. 6emethoxy-8-(4'amino -1-methylbutylan'lino), qui'noline res-described in the Journal othe=AmericanChemioal Society, vol. 68, page 1525, (1946). by one of the instant applicants and co-workers. This drug has very effective antimalarial? therapeutic properties, and, moreparticularly,.has been found to have dramatic effects: in. the treatment of certain types of arthritis. l

An impi ovjed technique for the production of primaquine and its homologshas now been found. Aceordinglmthis invention has; for its object the production.v ofprimaquine and its .homolo a, Another object is the production of primaquine'in superior yields and greater. purity than heretofore obtainable. Other objects will :beapparent as-theensuingdescription proceeds. 1

Thsecobfiects are accomplished, in accordance withthis invention wherein primaquine and.- its:

hoinologs areproduced'by reacting l iedibr'omopentaneL-or l,3+dibromobutane with potassium phthalimide-dissolved in acetone to -forma-.N-' ('bromoalkyl')phthalimide,, then reacting .this formed'compou'ndi with 6'- methox-y 8 aminoqulnolifie'. in a solvent: to. formfi-methoxy -firainthylxwe phthalimide alkylamino' quinoline, then treating this latter product with hydrazine hydrate to liberate the free base of primaquineior its homolog', and reacting thefree base withan acid to form a crystallizable salt: of primaquine orthe'corresponding homolog;

In the production-of :primaquinein accordance witli:. this invention the: "first step involves the condensation orireaction of "l-4 dibromo-pentane:

with potassium phthalimide in an acetone solution Duringthis reactionone bromine atom'at' the '1 end of, the pentane chain reacts with the alkali metal substituent of the phthalimide nuclus to produce asla lay-product potassium bromlde. The pentane radical is then directly united to the nuclearnitrogen atom of the phthalimide radical; It has been found that employing a stoichiometric excess of 1-4-dibromopentane is preferred inasmuch as the yields are tered to remove the formedpotass bro ,de

Z v 1 greater. Generally; from 50 to 190% excess of dibromopentaneis preferred on a molar bas s; The temperature of the reaction is gcnerally maintained at a temperature between dand C. The temperature of boiling aceton atmospheric conditions is about 56 C.

completion the race-tn, the som in};

and there fiuii condenser is'reinove I by an ordinary condenser." Thea tone an Tun reacted 1-4-dibromopentane, "are Idistilled'ofi' nd recover ed. Thecrude' product s distilled; avvacuum to give a yield of 4'-br6n io--1-ph ha idonentane of about 67% of the theoretical. The,produt isapaleyellow oil. jj The-seeond step in't'h synthesis is .to ra' 't 4bromol -phthalimidopefitafi (fi'iii'lafter ignated as CompoundI) With G-methoX'y-S noquinolinewhereby the .free bromine ate acts with thel hydrogen-atom attached amino nitrogen of the quirioline T' comp form 6-methoxy-B (bmethyl irphthaliimdob tylamino) quinoline. This]. reaction" isfacdm plished by heating the, reactants inla 'suit 1e sclvent suchaas ethanol while stirring ants; In-general 'the reaction coin'l ,ed iri. 60 to UZ-hqllls and .isIacilitated-by employing qui-nollne; compound in the proportions' of-I a ut 2 mo ls fthereot to 1 not of Co p 1 cormgaletion of the reaction, ,e'th i ixt enre pi et ep Washed with aqueous potassium with water-and finally-driedoifr magnes n1 fate. A yellowprodiict crystallizes-trams il-.- tion upon theadditionof; alcohol and there moval of ether that has-been identified. 6- we methoxy 8 (1; methyl -'4jplithal1niidobutyl amino) quinoline Compound II). s I

The thirdstep in the synthesis inyfol 4 'snthe vremoval of the phthalic ad erent which'j'l'eavje (hereinafter esignated? as ferred procedure.

tilled ofi until a solid begins to precipitate, the.

solid is then dissolved in aqueous potassium hydroxide and extracted intoether. The ether solution is then washed with water and dried over magnesium sulfate to yield an etherasolution of the free base of primaquinea In order to purify the same and secure it in crystallizable form,it is neutralized to a suitable salt with an acidsuch as hydrochloric acid, oxalic acid, and. preferably; phosphoric acid. By the addition of oxalic acid dissolved in absolute alcohol ayellow precipitate of primaquine half oxalate (primaquine'monooxalate) is secured. The precipitate is filtered ofi and recrystallizedfrom 80% ethanol or from methyl Cellosolve. The half-oxalate salt melts at 182.5185 C. and the diphosphate of primaquine melts at 197-198 "C.

*By replacing ll-dibromopentane with 1,3-dibromobutane, the corresponding homolog can similarly beprepared.

' The following illustrative examples will show how the invention may be carried out but it is not limited thereto: Example I.--4-bromo-1-phthalimidopentdne, (n

is ,vital as a solvent. When higher boiling sol-- vents, e. g. ethyl alcohol, dioxane or xylene were used, extensive elimination of the secondary bromine as hydrogen bromide occurred with the formation of easily polymerizing unsaturated com- A mixture of 2 moles of d-metho'xy-8-aminoquinoline and 1 mole of the side chain I in a liter of ethanol was refluxed with stirring for 72hours. After'cooling ether was added and-the solid wasfiltered oil; and washed with ether.

7 The filtrate was'washedwith aqueous potassium carbonate then with Water and dried over magnesium sulfate. After distilling off the ether, alcohol wasadded and the dark brown solution was boiled with decolorizing charcoal which re- I moved a considerable amount of red color. If

fairly pure starting materials, are used'a yellow product will crystallize slowly from the solution. The yieldis 40-50%.

' This material gave the following analytical figulres:

Calcd. for

Found: (1.70.97; H, 5.76. I s

Nors 1.The preceding represents the pre- Alternate satisfactory procedure is given in the following. V

.A mixture of 0.05 mole of side chain (II) and 0.05- mole of G-methoxy-B-aminoquinoline was added to 15 ml. of alcohol and a solution of 50 ml. of 0.05 mole of potassium dihydrogen phosphate buffered to pH 8 with about 0.05 mole of sodium hydroxide. at 75-430 for 79 hours.

The dark brown oily layer was separated from theaqueous solution, washed with potassium carbonate solution, diluted with ether, and dried over magnesium sulfate. The solvent was distilled off and the remaining oil was dissolved in alcohol. On cooling a 49% crude yield of solid was obtained.

Nors 2.-When crude side chain (not distilled) was used in the alkylation the product (II) remained dark even after charcoal treatment. In-

stead of crystallizing, a brown oil precipitated out.

, bromides of the unreacted nucleus and 0f the phthalimido quinoline compound (II). The two may be separated by extractions with hot benzene since 6-methoxy-8-aminoquinoline hydrobromi-de is rather insoluble in this solvent. After treating thebenzene extracts with excess aqueous potassium hydroxide, the solvent was distilled off. The resulting pale yellow oil may then be crystallized from alcohol yielding II.

Hydrolysis of the intermediate II .'Ihe phthalimido compound (II) was hydrolyzed by refluxing its alcoholic solution with the calculated amount of hydrazine hydrate for two hours. Alcohol was distilled off until solid began to be deposited. The solid was dissolved in aqueous potassium hydroxe ide and extracted into ether. After washing the ether solution with water it was dried over magnesium sulfate.

The half-oxalate was precipitated out of this ether solution by the addition of the calculated amount of oxalic acid dissolved in absolute alcoacid in 95% ethanol was added with shaking to 'a: Alight' dilute ether solution of the drug base. yellow solid precipitated.- ''On further additionof phosphoric acid in the amount calculated to form the diphosphate, this yellow solid turned orange and oily. After decantatio'n of the solventthe oil crystallized on addition of alcohol. After recrystallization from alcohol the diphosphate melted at 197-198 C. It gavethe followinganalytical figures:

'Calcd. for C15H21N3O.2H3PO42 c, 39.56; 5.97.- Found: C, 40.16; H, 6.38.

NOTE 1.-'I'he free drug base'decomposes on 'attempted vacuum distillation no matter how high the vacuum. It istherefore necessary to precipl tate the salt directly from a solution of'the base:

Example Ila-Using excess 6-met h 0my 8'-" amino qui olinepreliminary heating without solvent A mixture of 0.05mole of 4-bromo -l-phthalimidopentane and 0.1 mole of 6-methoxy-8- aminoquinoline was heated in an oil bath'with stirring over a half hour period up to 125. Heating was continued for an hour at -105. During this heating process some solid material was;

The mixture was stirred and heated amass of 6 -1rnethbxy-8 aminoquinoline. -hydrobromide 1 5 was filtered off; i The remaining brown liquid was i. swirled-with potassium carbonate solution-and extracted with ether. The etherlayer was driediover magnesium sulfate-- and" the solvent-was removed.

Theoilyresidu'ewas distilled-.1103-l27 at 7-10 microns. Solidbeg'ar'ito' precipitate and the distillation had to .be stopped. Ether was added to the distilling flask." "Ihesolid 'did'not dissolve but th'e glassy material a'tthdbottomuof the flask did." About 3.3 g. of solid was filteredrofifi".= On' recrysw tallization from alcohol orange needle-like C y tals were obtained, M. P. 235. This may be a dialkyl'ated product.

The "ether' solutionwas""evapora-ted aridthe A' mixture of .0.05moljeof ,,4-bromo:-"I;phthal"i.

aminoquinoline in ml. alcohol was refiu'xedbn" the steam bath for 67 hours. The crystalline 6- methoxy-B-aminoquinoline hydrobromide which was filtered oif of the reaction mixture weighed 9 g. On the basis of this amount of hydrobromide recovered, about 71% of the side chain was used in the reaction.

The alcohol filtrate was shaken with an aqueous potassium carbonate solution and extracted with ether. The combined ether layers were 40 washed with water, dried over magnesium sulfate and the ether was distilled 011.

The oily material which remained was not distilled as in previous cases but was crystallized from alcohol, with some difficulty. A total of 9.9 g. was obtained, representing a 51 yield of intermediate phthalimido compound.

Example IV.Synthesis of 4-b1'omo-1-phthalimzdopentane 5 A mixture of 1.0 mole of potassium phthalimide and 1.5 mole of 1,4-dibromopentane in 1000 ml. of

.acetone was refluxed with vigorous stirring for thirty hours, or until the mixture was neutral to litmus. 55

After cooling, potassium bromide was filtered ofi and washed with acetone. The solvent and unreacted dibromopentane were distilled off of the filtrate at water pump pressure.

The product was distilled. It distilled at' about 120-130/.l5 mm.; a 67% yield of pure product was obtained.

Exam/ple V.--3-brmno-1-phthalimidobutane A mixture of 2 moles of 1,3-dibromobutane and 1.5 moles of potassium phthalimide in 1.5 liters of acetone was stirred and refluxed for 24 hours. After filtering ofi potassium bromide and washing with acetone, the solvent and excess 1,3-dibromobutane were distilled off. The residue consisted 70 of a dark viscous oil, about 76% crude yield, which was used directly in the subsequent alkylation without further purification. An analytical sample was obtained by distillation at about 181/0.3

mm. as a pale yellow oil.

cared: ror': cm'mznmoit 10351501152; 1.- Found:C,51.46;H,4.35.

Example L-1s memos 1-;8- es-amnc-i mm i r propylammo)Quinolifl A 'gmixtureof 2 moles of 6-inethoxy--;8-'amino--; quinoline: and 1 mole of j '3'-br'om'o-=l-phthaliniido but'aneina-litfof ethanol wasrefiuxed jwit-hsti-r 5 ringfor' f'727hoursti" After cooling; ether-was adde and other: solid -hydrobrbn idef of T 6-methoxy aminoquinolinewas"filtered off and: washed -'wit ethrx -.ii t fat fw siiv h dw a e u sium carbb ater t n w h'w t na d' dr f fiv magnesium sulfate: After'distilling off the' ether, alcoholwas added .and the dark brown solution was boiled'with'decolorizing charcoal. The product crystallized rather slowly and the addition of seed crystals was usually necessary. The yield is about 40% An analytical sample of this material recrystallized several times from alcohol gave the following figures:

Calcd. for C22H-21N3O32 C, 70.38; Found: C, 70.47; H, 5.53.

The above phthalimido compound was hydrolyzed byrefiuxing itsalcoholic solution with the calculated amount of :hydrazine hydrate :fortwo hours: Alcohol was distilled. oif until solid began tobe'ideposited. :1: Theso-lid'was dissolved in aque-. ous potassium hydroxide and extracted into ether. After washing the ether solution with water it was dried over magnesium sulfate.

The di-phosphate was precipitated out of this ether solution as follows: A solution of the calculated amount of phosphoric acid in ethanol was added with shaking to the dilute ether solution of the drug base. An oily orange deposit of the diphosphate resulted which crystallized on addition of alcohol after decantation of the original ether solution. After recrystallization from aqueous alcohol, the diphosphate melted at 210-211". It gave the following analytical figures:

Calcd. for C14H19N3O-2H3PO4: C, 38.09; H, 5.71. Found: C, 38.52; H, 6.07.

Since many apparently differing embodiments of this invention will occur to one skilled in the art, it is obvious that many changes can be made 0 in the specific preferred embodiments disclosed above without departing from the spirit and scope of this invention.

What is claimed is:

1. A process for the production of primaquine which comprises reacting 1,4-dibromopentane with potassium phthalimide dissolved in boiling acetone to form N-(4-bromopentyl) -phthalimide, then reacting N-(4-bromopentyl) phthalimide with fivmethoxy-8-aminoquinoline in a solvent to form 6-methoxy-8-(l-methyl-l-phthalimidobutylamino) quinoline, treating this latter product with hydrazine hydrate to liberate the free base of primaquine, and reacting the free base with oxalic acid to form the mono-oxalate salt of primaquine.

2. A process for the production of primaquine which comprises reacting 1,4-dibromopentane with potassium phthalimide dissolved in boiling acetone to form N-(l-bromopentyl)-phthalimide, then reacting N-(4-bromopentyl) phthalimide with 6-methoxy-8-aminoquinoline in a solvent to form 6-methoxy-8-(1-methyl-4-phtha1- imidobutylamino) quinoline, treating this latter product with hydrazine hydrate to liberate the free base of primaquine, and reacting the free 7'11; baseiwithiphosphoric acidito form, therdi'phosg phate salt of primaquine.

3. A process for the production of fi rnetho xy V 8-(3: amino 11- methy1propy1amin0) 'quinoline which comprises reacting 1,3 -dibrom0butane with potassium phthalimide dissolved in boiling acetone to form N-(3- bromobutyl) -phtha1imide, then reacting N;'(3 bromobutyb-phthalimid with G-methOXy-S-aminoquinoline in 'a solvent to I form 6-me'thoxy-8-(ii phthalimido 1 methylpropylamino) quinoline, treating this latter p'roductwith hydrazine hydrate to liberate the free base of 6-methoxy-8-(3-amino-l-methylpropyl amino) quinoline, and reacting the free base with phosphoric acid to form the diphosphate salt of 6 rnethoxy-8-(3 amino-l-methylpropylamino)" quinoline. 'L 51. Aprocess foffthe production of a salt of ,al (compound 'ha'vingthe formula wherein n is an integer selected from the group consisting of 2 and 3, which comprises heating a dibromoalkane selected from the group consisting of 1,4-dibromopentane and 1,3-dibromobutane with potassium; phthal i inide in a solvent to a temperature of about C. to C., then r ctin it e. stormed N-bromoalkyllihthalmfiag form; a fi-methoxy-S- g 1 methylphthaliniidoalkyh" m nolrqu nol na reat n h a t product'f withwh cl az ne hydrate. t l b e h freeibas' y Splitti ,Ofl: phthalic acid, and'reacting the. free base with an acid capable of forrriinga hygroscopic salt.

- ROBERT C, DI',

QIQE EANQ YWEB -f 7 ,TLTZF EtfiR WES'Q E The 'followingureferences are ,ofrrecord in the filaoffthis patent: V j-{UMTE STATES-PATENTS- Number Name Date 1,938,047

' OTHER REFERENCES Elder-field et a1.: J. Am. Chem. Soc., vol. 68, pp."

Cope et al.: J';Am.;Chem. Soc., vol. 554-561 (February 1949).

Baldwin et al.: J. Chem. Soc. (London), .1934, pp. 1264-1268.

Sidgwick: Organic Chemistry of Nitrogen," (Oxford University Press; New York; 1942), pp. 14 and 15. i

Schonhofer et a1. Dec. 5,1933 

4. A PROCESS FOR THE PRODUCTION OF A SALT OF A COMPOUND HAVING THE FORMULA 